July 14, 2003
Previous work has shown that Trizivir alone is more likely to be associated with virologic breakthrough for patients who have previously been treated with mono or dual non-suppressive NRTI therapies. Many of these patients harbor the M184V mutation that confers resistance to lamivudine (3TC, Epivir); others have thymidine analogue mutations (TAMs) that produce resistance to AZT (zidovudine, Retrovir).
This prospective, observational study was done to see if the popular combination of Trizivir (abacavir + AZT + 3TC) and tenofovir (TDF, Viread) would be effective (have good antiviral activity) in patients with either proven or suspected NRTI resistance mutations.
The majority (17 of 20 patients) who entered into this study had a viral load less than 75 copies/mL at study entry. All 20 patients were changed to Trizivir plus tenofovir primarily because of lipid abnormalities or simplification of regimen. They all had archived or suspected NRTI resistance mutations. Those with suspected mutations such as M184V had previously been on a non-suppressive regimen that contained 3TC. The majority of patients did have documented archived NRTI mutations.
For practical purposes, this study can really be considered a switch since 17/20 had a viral load less than 75 copies/mL. The majority (13/20) were on NNRTI-based therapy at the time of switch.
From an overall perspective, this combination was successful in this group of patients. Of the 17 patients that were switched for lipid or simplification reasons, only two patients experienced virologic breakthrough. Both of these patients broke through early at four weeks and had M184V and multiple TAMs. Of the three patients with detectable virus at time of switch, all three were successfully controlled (less than 400 copies/mL) with Trizivir plus tenofovir. This study showed successful virologic outcomes (available for 13/20 patients) at week 24 follow up.
Among patients switched for lipid abnormalities, there were significant improvements in cholesterol and triglyceride levels. At week 24 there was a 46 percent reduction in triglycerides and a 28 percent reduction in total cholesterol.
The significance of this study relates to the fact that lipid issues are important for many patients with HIV infection, especially those with multiple cardiac risk factors. Many of these patients are on a PI-based regimen and prior switch studies have mainly focused on a change to an NNRTI-based regimen. In previous studies, switching PI-based therapy to triple nucleoside therapy was associated with higher rates of virologic breakthrough compared to an NNRTI switch. This study indicates that a four-drug nucleoside (although tenofovir is really a nucleotide) therapy may be an alternative for some patients, even those with known or suspected limited reverse transcriptase (RT) resistance mutations.
The weakness of this pilot study is, of course, its small size and short duration. We also do not know which NNRTI some of these patients were switched from, nor do we know the breakdown of lipid abnormalities according to pre-switch therapy. If there were significant reductions in lipids after the switch from an NNRTI-based regimen, this would be an interesting finding.
This study was presented by the Tower ID Medical group in Los Angeles and sponsored by GlaxoSmithKline, the maker of Trizivir.
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